STRUCTURAL STUDIES ON AMINOGLYCOSIDE PHOSPHOTRANSFERASES

氨基糖苷磷酸转移酶的结构研究

• 批准号: 8362077
• 负责人: CLYDE A SMITH
• 金额: $ 0.06万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362077
• 关键词: Aminoglycoside resistance; Aminoglycosides; Antibiotic Resistance; Antibiotics; Binding; Complex; Crystallization; Enterococcus; Enterococcus faecium; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Family; Funding; Gentamicins; Grant; Kanamycin; Kanamycin Kinase; Mediating; Multienzyme Complexes; National Center for Research Resources; Phosphotransferases; Principal Investigator; Publishing; Radiation; Research; Research Infrastructure; Resistance; Resources; Source; Streptomycin; Structure; Tobramycin; United States National Institutes of Health; cost; design; hydroxyl group; structural biology; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A major factor in the emergence of antibiotic resistance is the existence of bacterial enzymes that chemically modify common antibiotics. One such family of anti-bacterials to which there is now almost universal resistance are the aminoglycosides (e.g. kanamycin, tobramycin and gentimicin). High level resistance to gentamicin in enterococci is mediated by a group of four phosphotransferases belonging to the APH(2?) sub-family of enzymes which phosphorylate at a specific hydroxyl group on the antibiotic, using ATP as a cosubstrate. An understanding of how these enzymes bind and deactivate the aminoglycosides will provide valuable information for the design of specific inhibitors of these enzymes. We are studying all four of the APH(2?) phosphotransferases, APH(2?)-Ia and APH(2?)-IIa from Enterococcus faecium, APH(2?)-IIIa from E. gallinarum, and APH(2?)-IVa from E. casseliflavus. The three dimensional structures of the binary gentamicin complex and a ternary AMPPCP-streptomycin complex of APH(2?)-IIa have been determined and published and the crystallization conditions for APH(2?)-IIIa and APH(2?)-IVa established. Both the APH(2?)-IIIa and APH(2?)-IVa structures have been solved. Studies will focus on solving structures of binary and ternary complexes of these enzymes.

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